Posttranslational modifications of tau protein in wildtype mice and a new model of neurofibrillary tangle formation: Implications for Alzheimer's disease.

摘要

Although neurofibrillary tangles, plaques and cell loss are all prominent neuropathologic features of Alzheimer's disease, and each has been intensively studied, the relationship between them remains largely unresolved. This is in part due to a lack of an appropriate model system in which to study the initiating events underlying all three hallmarks. The predominant hypothesis has been that if there are no mutations on tau, as is the case in Alzheimer's disease, there must be an additional factor to initiate tau pathology. This factor has long been held to be the small peptide fragment beta-amyloid, which accumulates as extracellular fibrils in senile plaques. Here, however, we show that neurofibrillary tangle formation can develop from non-mutant human tau, in the absence of any other exogenous factors, including beta-amyloid.; Neurofibrillary tangles are formed from the intracellular accumulation of the microtubule-associated protein tau as aggregated filaments. In the process of accumulating as neurofibrillary tangles tau undergoes significant posttranslational modification, including; hyperphosphorylation, conformational change, and abnormal localization. There are qualitative and functional differences between the six isoforms of human tau that are generated from alternative splicing of a single tau gene. These isoforms can be separated into two groups, either 3R or 4R, depending on the inclusion or exclusion of an imperfect repeat region coded for by exon 10. Alterations in the ratio of 3R and 4R isoforms, normally present in equal amounts in humans, have been linked to a number of neurodegenerative diseases that develop neurofibrillary tangles.; To create a model system in which to examine a human profile of tau isoforms in the absence of the 4R-mouse tau, we have generated mice that exclusively express the human tau isoforms, herein referred to as htau mice. These mice develop evidence of neurofibrillary tangle formation, including; cell body accumulation of hyperphosphorylated tau, paired helical filaments and thioflavine-S positive neurons. The tau pathology in these mice is accompanied by quantitative and qualitative evidence of cell death, thus supporting a direct link between aggregated wildtype tau and neurodegeneration.